Pyroglutamate Abeta pathology in APP/PS1KI mice, sporadic and familial Alzheimer’s disease cases

The presence of Aβ_pE3 (N-terminal truncated Aβ starting with pyroglutamate) in Alzheimer’s disease (AD) has received considerable attention since the discovery that this peptide represents a dominant fraction of Aβ peptides in senile plaques of AD brains. This was later confirmed by other reports investigating AD and Down’s syndrome postmortem brain tissue. Importantly, Aβ_pE3 has a higher aggregation propensity, and stability, and shows an increased toxicity compared to full-length Aβ. We have recently shown that intraneuronal accumulation of Aβ_pE3 peptides induces a severe neuron loss and an associated neurological phenotype in the TBA2 mouse model for AD. Given the increasing interest in Aβ_pE3, we have generated two novel monoclonal antibodies which were characterized as highly specific for Aβ_pE3 peptides and herein used to analyze plaque deposition in APP/PS1KI mice, an AD model with severe neuron loss and learning deficits. This was compared with the plaque pattern present in brain tissue from sporadic and familial AD cases. Abundant plaques positive for Aβ_pE3 were present in patients with sporadic AD and familial AD including those carrying mutations in APP (arctic and Swedish) and PS1. Interestingly, in APP/PS1KI mice we observed a continuous increase in Aβ_pE3 plaque load with increasing age, while the density for Aβ_1-x plaques declined with aging. We therefore assume that, in particular, the peptides starting with position 1 of Aβ are N-truncated as disease progresses, and that, Aβ_pE3 positive plaques are resistant to age-dependent degradation likely due to their high stability and propensity to aggregate.     

Prevalence and prognostic impact of subclinical cardiovascular disease in individuals with the metabolic syndrome and diabetes

Data are limited regarding prevalence and prognostic significance of subclinical cardiovascular disease (CVD) in individuals with metabolic syndrome (MetS). We investigated prevalence of subclinical CVD in 1,945 Framingham Offspring Study participants (mean age 58 years; 59% women) using electrocardiography, echocardiography, carotid ultrasound, ankle-brachial blood pressure, and urinary albumin excretion. We prospectively evaluated the incidence of CVD associated with MetS and diabetes according to presence versus absence of subclinical disease. Cross-sectionally, 51% of 581 participants with MetS had subclinical disease in at least one test, a frequency higher than individuals without MetS (multivariable-adjusted odds ratio 2.06 [95% CI 1.67-2.55]; P < 0.0001). On follow-up (mean 7.2 years), 139 individuals developed overt CVD, including 59 with MetS (10.2%). Overall, MetS was associated with increased CVD risk (multivariable-adjusted hazards ratio [HR] 1.61 [95% CI 1.12-2.33]). Participants with MetS and subclinical disease experienced increased risk of overt CVD (2.67 [1.62-4.41] compared with those without MetS, diabetes, or subclinical disease), whereas the association of MetS with CVD risk was attenuated in absence of subclinical disease (HR 1.59 [95% CI 0.87-2.90]). A similar attenuation of CVD risk in absence of subclinical disease was observed also for diabetes. Subclinical disease was a significant predictor of overt CVD in participants without MetS or diabetes (1.93 [1.15-3.24]). In our community-based sample, individuals with MetS have a high prevalence of subclinical atherosclerosis that likely contributes to the increased risk of overt CVD associated with the condition.     

Endothelium-dependent vasodilation in conduit and resistance vessels in relation to the endothelial nitric oxide synthase gene

Single nucleotide polymorphisms (SNPs) in the endothelial nitric oxide synthase (NOS3) gene have been related to endothelium-dependent vasodilation in either conduit or resistance arteries with divergent results. In the Prospective Study of the Vasculature in Uppsala Seniors study, 959 participants aged 70 (51% men) were evaluated with brachial artery ultrasound to assess flow-mediated vasodilation (FMD; reflecting conduit arteries) and invasive forearm technique with intrabrachial infusion of acetylcholine (endothelium-dependent vasodilation (EDV); reflecting resistance arteries). The 23 SNPs analysed by minisequencing captured >90% of the common genetic variation in the NOS3 gene, using the HapMap population of European ancestry (CEU) as reference. One SNP (Glu298Asp) was related to FMD (nominal P=0.0018), but not to EDV (nominal P=0.76) after adjustment for sex, systolic blood pressure, diastolic blood pressure, pulse rate, antihypertensive treatment, total cholesterol, high-density cholesterol, lipid-lowering medication, fasting glucose, antidiabetic medication, body mass index, current smoking and prior diagnosis of cardiovascular disease. This relation was significant in both men and women in sex-specific analyses, and remained significant after adjusting for multiple testing (empirical P=0.029 from bootstrap resampling). None of the constructed haplotypes were related to vasodilation. The Glu298Asp SNP in the NOS3 gene was related to endothelium-dependent vasodilation in conduit, but not in resistance arteries. This SNP has previously been related to coronary heart disease, and our findings should stimulate to replication and exploration of the association of NOS3 variation with endothelial function in other settings.     

Circulating ghrelin, leptin, and soluble leptin receptor concentrations and cardiometabolic risk factors in a community-based sample

CONTEXT: The conjoint effects and relative importance of ghrelin, leptin, and soluble leptin receptor (sOB-R), adipokines involved in appetite control and energy expenditure in mediating cardiometabolic risk, is unknown. OBJECTIVE: The objective of the study was to study the cross-sectional relations of these adipokines to cardiometabolic risk factors in a community-based sample. DESIGN, SETTING, AND PARTICIPANTS: We measured circulating ghrelin, leptin, and sOB-R in 362 participants (mean age 45 yr; 54% women) of the Framingham Third Generation Cohort. MAIN OUTCOME MEASURES: Body mass index, waist circumference (WC), blood pressure, lipid measures, fasting glucose, smoking, and metabolic syndrome (MetS) were measured. RESULTS: Ghrelin and leptin concentrations were significantly higher in women (P < 0.0001). In multivariable models, ghrelin was inversely associated with age and systolic blood pressure, and leptin was positively related to body mass index and WC. sOB-R was positively associated with age, total cholesterol, and fasting glucose and inversely with WC and high-density lipoprotein cholesterol. Ghrelin and sOB-R concentrations were significantly lower with number of MetS components (P for trend = 0.022 and < 0.0001, respectively), whereas leptin concentrations were higher (P for trend = 0.0001). Relating all adipokines to MetS conjointly, higher ghrelin and leptin concentrations were associated with decreased and increased odds of MetS (odds ratio 0.55, P < 0.0001; odds ratio 4.44, P = 0.0002, per 1 sd increase of respective log adipokine). CONCLUSIONS: In our community-based sample, we observed a sexual dimorphism in circulating ghrelin and leptin concentrations. Ghrelin, leptin, and sOB-R were associated with number of MetS components cross-sectionally, consistent with the hypothesis that these adipokines may have a central role in cardiometabolic risk.     

Cerebrovascular and ischemic heart disease in young adults born preterm: a population-based Swedish cohort study

Preterm birth is associated with overall cardiovascular mortality in young adulthood, but which specific conditions that underlie this association is unknown. We studied mortality and morbidity from cerebrovascular and ischemic heart disease in individuals born preterm. In a nationwide Swedish study, we included 1,306,943 individuals without congenital malformations born between 1983 and 1995, followed from 15 years of age to December 31st, 2010. Of these, 73,489 (5.6 %) were born preterm (<37 weeks of gestation). Cox proportional hazards regression analysis was used to calculate hazard ratios (HR) with 95 % confidence intervals (CI), after adjusting for maternal characteristics and birth weight for gestational age. Of 955 incident cases of cerebrovascular disease, 58 (6.1 %) occurred in preterm born subjects. The corresponding numbers of ischemic heart disease cases were 180 and 13 (7.2 %), respectively. Birth before 32 weeks was associated with a nearly twofold increased risk of cerebrovascular disease; adjusted HR, (95 % CI) = 1.89 (1.01–3.54) compared to term born individuals, whereas individuals born at 32–36 weeks were not at increased risk. Preterm birth was not associated with later ischemic heart disease; no cases of ischemic heart disease were recorded among those born before 32 weeks and the HR (95 % CI) for those born at 32–36 weeks of gestation was 1.45 (0.81–2.57), compared to term-born individuals. Birth before 32 weeks is associated with increased risk of cerebrovascular disease in young adulthood. Our data suggest that cardiovascular health promotion in follow-up programs after very preterm birth may be beneficial.     

The tau S305S mutation causes frontotemporal dementia with parkinsonism

Members of families with mutations in the tau gene are known to be heterogeneous in their clinical presentation, ranging from frontotemporal dementia to a clinical picture more resembling corticobasal degeneration or progressive supranuclear palsy. In this report, we describe a new phenotype for the tau S305S mutation, previously described as progressive supranuclear palsy. Clinically, the three affected family members showed alterations in personality and behaviour as well as cognitive decline and late levodopa-resistant parkinsonian symptoms, consistent with the diagnosis of frontotemporal dementia with parkinsonism linked to chromosome 17. One autopsied case displayed degeneration of the frontal and temporal lobes together with extensive tau pathology in both neurones and glial cells. Sarkosyl-soluble and -insoluble tau extracted from frontal cortex revealed a ratio shift with decreased levels of tau with three microtubule-binding repeats and increased levels of tau with four microtubule-binding repeats (4R tau). These findings provide further evidence for the clinical and pathological variation both within and between families with mutations in the tau gene. In addition, they support previous studies which demonstrate that the S305S mutation influences the splicing of tau exon 10 and results in an overproduction of 4R tau.